BackgroundRadiotherapy is one of the main therapeutic approaches for non–small cell lung cancer (NSCLC). However, radioresistant cancer cells can eventually cause tumor relapse and even fatal metastasis. It is thought that radioresistance and metastasis could be potentially linked by epithelial-mesenchymal transition (EMT). In this study, we established radioresistant NSCLC cells to investigate the potential relationship among radioresistance, EMT, and enhanced metastatic potential and the underlying mechanism involving liver kinase B1 (LKB1)-Salt-inducible kinase 1 (SIK1) signaling.MethodsThe radioresistant cell lines A549R and H1299R were generated by dose-gradient irradiation of the parental A549 and H1299 cells. The radioresistance/sensitivity was evaluated by Cell Counting Kit-8 assay, apoptosis analysis, and/or clonogenic cell survival assay. The EMT phenotype and the signaling change were assessed by Western blotting. The abilities of invasion and migration were evaluated by transwell assays and wound healing assays.ResultsThe radioresistant cell lines A549R and H1299R displayed mesenchymal features with enhanced invasion and migration. Mechanistically, A549R and H1299R cells had attenuated LKB1-SIK1 signaling, which leaded to the up-regulation of Zinc-finger E-box-binding homeobox factor 1 (ZEB1)—a transcription factor that drives EMT. Re-expression of LKB1 in A549R cells reversed the EMT phenotype, whereas knockdown of LKB1 in H1299R cells further promoted the EMT phenotype. Moreover, re-expression of LKB1 in A549 cells increased the radiosensitivity, whereas knockdown of LKB1 in H1299 cells decreased the radiosensitivity.ConclusionsOur findings suggest that attenuated LKB1-SIK1 signaling promotes EMT and radioresistance of NSCLC cells, which subsequently contributes to the enhanced metastatic potential. Targeting the LKB1-SIK1-ZEB1 pathway to suppress EMT might provide therapeutic benefits.
BackgroundThis pilot trial is designed to determine whether PET/CT-guided radiotherapy dose escalation can improve local control while minimizing toxicity for the treatment of locally advanced nasopharyngeal carcinoma.Methods67 patients were randomized into the three treatment arms: conventional chemoradiotherapy (group A), CT-guided dose escalation chemoradiotherapy (group B) and PET/CT-guided dose escalation chemoradiotherapy (group C). Radiotherapy was delivered using the simultaneous modulated accelerated radiation therapy (SMART) technique in the dose-escalation treatment arms. Patients received concurrent and adjuvant chemotherapy.ResultsThe use of PET/CT significantly changed the treatment volume delineation of the gross tumor volume. 3-year local progression-free (LPF) survival rates of three groups were 83.3%, 90.9% and 100%, respectively. The 3-year regional progression-free survival (RPFS) rates were 95.8%, 95.5% and 100%, respectively. The 3-year disease free survival (DFS) rates were 79.2%, 86.4% and 95.2%, respectively. The 3-year overall survival (OS) rates were 83.3%, 90.9% and 95.2%, respectively. The 3-year disease-free survival (DFS) rates were 79.2%, 86.4% and 95.2%, respectively. No patient had grade 4 late toxicity.ConclusionsPET/CT-guided dose escalation radiotherapy is well-tolerated and appears to be superior to conventional chemoradiotherapy for locally advanced NPC.Trial RegistrationClinicalTrials.gov NCT02089204
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.